Etoricoxib

Molecular formula C18H15CIN2O2S Molecular weight 358.84 CAS Registry No 202409-33-4 

Sample preparation Condition a 1 mL 30 mg Oasis HLB SPE cartridge with 1 mL MeOH and 1 mL water. Mix 200 LL plasma with 20 p.L 500 ng/mL IS in water, centrifuge at 12 000 g, add to the SPE cartridge, wash with 1 mL MeOH water 5 95, dry under reduced pressure for 5 min, elute with 2 mL MeCN ethyl acetate 50 50. Evaporate the eluate to dryness under reduced pressure at 45°, reconstitute the residue with 200 m-L mobile phase, inject a 15 p,L aliquot. 

Detector MS, PE Sciex API 3000 triple quadrupole, turbo ionspray, positive ion mode 5400 V and 400°, nebulizer gas nitrogen at 1.49 L/min, curtain gas nitrogen at 1.25 L/min, collision gas nitrogen, collision energy 43 eV, m/z 359.0-280.1 

Brautigam, L. Nefflen, J.U. Geisslinger, G. Determination of etoricoxib in human plasma by liquid chromatography-tandem mass spectrometry with electrospray ionisation, J.Chromatogr.B, 2003, 788, 

Sample preparation Inject a 10 itL aliquot of a 100 p.g/mL solution in MeCN water 

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Celecoxib, which has a low selectivity for COX-2 compared to COX-1, is still available, although its more selective successor, valdecoxib has been withdrawn. Etoricoxib, the successor to rofecoxib, is marketed in Europe but not in the USA. In a large multinational clinical trial, etoricoxib caused no more thromboembolic events than diclofenac, but after 18 months the incidence of gastrointestinal ulcers and bleeding was the same for both drugs [4]. 

Cannon CP, Curtis SP, FitzGerald GA et al (2006) Cardiovascular outcomes with etoricoxib and diclofenac in patients with osteoarthritis and rheumatoid arthritis in the Multinational Etoricoxib and Diclofenac Arthritis Long-term (MEDAL) programme a randomised comparison. Lancet 368 1771-1781... 

It follows that drugs that selectively inhibit COX-2 should cause fewer side effects than those that inhibit both COX-1 and COX-2. At therapeutic doses, all currently available NSAIDs, with the excqrtion of celecoxib, etoricoxib, lumiracoxib and parecoxib (the prodrug of valdecoxib), are non-selective and inhibit both COX isoforms. 

The development of the COXIBs has been based on the hypothesis COX-1 is the physiological COX and COX-2, the pathophysiological isoenzyme. Inhibition of the pathophysiological COX-2 only is assumed to result in fewer side effects as compared to non-selective inhibition of both COX isoenzymes (Fig. 2). Celecoxib, etoricoxib and lumiracoxib (in some countries also parecoxib) are the only COXIBs currently approved. 

Highly selective COX-2 inhibitors - coxibs (rofecoxib, celecoxib, or less popular - valdecoxib, etoricoxib parecoxiband lumiracoxib) - were found to be well tolerated in a series of placebo-controlled clinical trials [8]. However, rofecoxib and valdecoxib have been withdrawn from the market because of an increased incidence... 

Indomethacin and sulindac are slightly selective for COX-1. Meclofenamate and ibuprofen are approximately equipotent on COX-1 and COX-2, whereas celecoxib = diclofenac < rofecoxib = lumiracoxib < etoricoxib in inhibition of COX-2 (listed in order of increasing average selectivity). Aspirin acetylates and inhibits both enzymes covalently. Low doses (< 100 mg/day) inhibit preferentially, but not exclusively, platelet COX-1, whereas higher doses inhibit both systemic COX-1 and COX-2. 

Matsumoto AK et al A randomized, controlled, clinical trial of etoricoxib in the treatment of rheumatoid arthritis. J Rheumatol 2002 29 1623. [PMID 12180720]... 

Celecoxib, rofecoxib, valdecoxib, parecoxib sodium, and etoricoxib all belong to this chemical class. 

Synthesis A number of synthetic strategies to the COX-2 specific inhibitor etoricoxib have been described (Dube et al. (Merck Frosst), 1998 Davies et al., 2000 Sobera et al., 2001a). In schemes 17-20 the two major routes via a dichloropyridine derivative or a ketosulfone, respectively, as the key intermediates are discussed. 

Finally, compound (iv) is condensed with either trimethyl(6-methyl-3-pyridyl)tin or the boronate ester by means of Pd(PPh3)4 to afford etoricoxib. The metallated pyridine (vii) is obtained by esterification of 3-hydroxy-2-methylpyridine with triflic anhydride to give the corresponding triflate, which is treated with a tin reagent to yield the target tin intermediate. The boron lithium salt (viii) is prepared by treatment of 5-bromo-2-methylpyridine with butyllithium followed by addition of triisopropyl borate. 

Scheme 18 Condensation pathways from the key intermediate 2,5-dichloro-3-(4-(methylsulfonyl)phenyl) pyridine (iv) with the tin or boronate derivative, respectively, to afford etoricoxib.

Scheme 19 Synthetic pathways to the ketosulfone (ix) as the key intermediate for the etoricoxib synthesis.

Finally etoricoxib can be obtained by several related cylization reactions ... 

Plasma peak concentrations are achieved within 1.0 to 1.5 h after administration in healthy volunteers and the elimination half-life is about 15 h. Etoricoxib is 60% metabolized via members of the cytochrome P450 3A family (Kassahun et al., 2001). In vitro studies provide no evidence for active metabolites with respect to COX-1 and COX-2 (Chauret et al., 2001). 

Scheme 20 Different cyclization pathways of of the ketosulfone to etoricoxib.

The metabolic profile of etoricoxib is shown below (Chauret et al., 2001) ... 

Scheme 21 In vitro metabolic pathways of etoricoxib. Trade name Arcoxia (US)...

Trimble, L. A., Nicoll-Griffith, D. A. . In vitro metabolism considerations, including activity testing of metabolites, in the discovery and selection of the COX-2 inhibitor etoricoxib (MK-0663), Bioorg. Med. Chem. Lett. 2001, 11, 1059-1062. 

Kassahun, K., McIntosh, I. S., Shou, M., Walsh, D. J., Rodeheffer, C., Slaughter, D. E., Geer, L. A., Flalpin, R. A., Agrawal, N., Rodrigues, A. D. Role of human liver cytochrome P4503A in the metabolism of etoricoxib, a novel cyclooxygenase-2 selective inhibitor, Drug Metab. Dispos. 

Visco, D., Girard, Y., Prasit, P., Zamboni, R., Rodger, I.W., Gresser, M., Ford-Hutchinson, A.W., Young, R.N., Chan, C.C. Etoricoxib (MK-0663) preclinical profile and comparison with other agents that selectively inhibit cyclooxygenase-2, J. Pharmacol. Exp. Ther. 2001, 296, 558-566. 

Etoricoxib 102, a 2,3-bipyridine derivative, has been used as a nonopioid analgesic <2003EP0912518>. A bis-tetrahydroisoquinoline derivative, tetrandrine 103, has been used an analgesic and is present in the Chinese drug han-fang-chi . 

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